High-Atom Economic Approach to Prepare Chiral α-Sulfenylated Ketones

Article abstract of DOI:10.1021/acs.joc.9b01424

Chiral α-sulfenylated ketones are versatile building blocks, although there are still several limitations with their preparation. Here we report a new two-step procedure, consisting of Pd-catalyzed hydrothiolation of propargylic alcohols followed by an enantioselective Rh isomerization of allylic alcohols. The isomerization reaction is the key step for obtaining the ketones in their enantioenriched form. The new methodology has a high atom economy and induces good to high levels of enantioselectivity; no waste is produced. A mechanism involving a Rh-hydride-enone intermediate is proposed for the isomerization reaction.

Full text of DOI:10.1021/acs.joc.9b01424

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Note
A high atom economic approach to prepare chiral #-sulfenylated ketones
Jèssica Margalef, Rahul A. Watile, Thanya Rukkijakan, and Joseph S. M. Samec
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01424 • Publication Date (Web): 06 Aug 2019
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The Journal of Organic Chemistry
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A high atom economic approach to prepare chiral α-sulfenylated
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‡
†
†
,†
Jèssica Margalef , Rahul A. Watile , Thanya Rukkijakan , Joseph S. M. Samec*
†Department of Organic Chemistry, Stockholm University, 106 91 Stockholm, Sweden
‡Department of Physical and Inorganic Chemistry, Universitat Rovira i Virgili, 43007 Tarragona, Spain
*joseph.samec@su.se
ABSTRACT: Chiral α-sulfenylated ketones are versatile building blocks, although there are still several limitations with
their preparation. Here we report a new two-step procedure, consisting in a Pd-catalyzed hydrothiolation of propargylic
alcohols followed by an enantioselective Rh-isomerization of allylic alcohols. The isomerization reaction is the key step for
obtaining the ketones in their enantioenriched form. The new methodology has high atom economy, no waste is produced
and induces good to high levels of enantioselectivity. A mechanism involving a Rh-hydride-enone intermediate is proposed
for the isomerization reaction.
sulfenylating agents used in this transformation, generate
stoichiometric amounts of chemical waste. In addition, the
substrate scope is quite narrow since cyclic and/or activated
carbonyl compounds such as oxindoles , β-ketoesters,
azalactones, and benzolactones
1a). As far as we know, only two efficient catalytic methodologies
have been reported for the preparation of chiral α-sulfenylated
ketones (Scheme 1b). However, these methodologies have low
atom economy.
INTRODUCTION
Finding efficient catalytic systems able to promote new carbon-
sulfur (C-S) bonds is a challenge, since sulfur reagents are known
to poison metallic catalysts. Sulfur is present in several synthetic
drugs and biologically active natural products. Indeed,
approximately 20% of the approved FDA drugs contain sulfur
1
0
11
1
2
11e,g
are often employed (Scheme
1
2
13
atoms and 31 of them contain a thioether moiety. In addition,
molecules bearing a thioether on a stereogenic carbon are also
important from the point of view of organic synthesis, since they
can be transformed to other relevant molecules in an
Scheme 1. Catalytic routes to prepare chiral α-
sulfenylated ketones
3
3
enantioespecific fashion. The sp -hybridized C-S bond in
thioethers can be activated towards other functional groups if
desired. For example, it could participate in cross-coupling
a) Typical methodology: electrophilic -sulfenylation
O
O
4
5
6
reactions, and be transformed into olefins , organometallics and
R'
Catalyst
O
R'
ZH
+
R''SZ
X
+
X
3,7
*
halides .
H
SR''
Chemical waste
O
Common substrates:
O
O
O
O
O
X
R1
(
H3C)2N
S
N
N
OR
-ketoesters
Ar
azalactones
S
X = O oxindoles
X = NH benzolactones
b) Existing methodologies for asymmetric -sulfenylation of ketones
anti-leishmanial agent9a
anti-inflamatory agent9b
- Coltart (2011):
Br
NOH
NOH
O
O
O
1) NaHCO3
SR3
IBX
SR3
Cl
2) Organocatalyst / R SH R1
R1
R1
3
R
*
2
N
R2
R2
R
S
O
S
30-88% ee
- Denmark (2014):
OSiMe3
O
O
O
NH2
S
R
*
SPh
R
1) Organocatalyst
R1
anti-cancer agent9c
anti-tumor agent9d
R1
+
N
SPh
2
) HF·Py
O
50-96% ee
Figure 1. Chiral α-sulfenylated compounds with biological
activity.
c) Current work
O
The enantioselective α-sulfenylation of carbonyl compounds is
currently the most straightforward methodology for preparing
highly versatile building blocks bearing a sulphide moiety.
Furthermore, chiral α-sulfenylated carbonyl compounds have
HO
OH
3 2
RhCl .H O
(S)-DIFLUOROPHOS
Pd(OAc)2
R1
R1
R1
+
SR2
1
b,d,8
SR2
2
R SH
5
0 to >99% (R)
Readily available
starting materials
9
shown biological activity (Figure 1). However, the typical
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In 2011, Coltart and co-workers reported the first catalytic
asymmetric process to prepare such type of compounds, via in situ
were determined using 1,3,5-trimethoxybenzene as internal-
standard and er through HPLC analysis.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3a
formed nitrosoalkenes.
The main advantage of this
transformation is that simple thiols instead of electrophilic sulphur
reagents can be employed. Later, Denmark et al. published an
enantioselective Lewis based-catalyzed α-sulfenylation of silyl
RESULTS AND DISCUSSION
Initially, several bisphosphines were screened in the
isomerization of allylic alcohol 1a. In general, only biaryl-type
phosphines were able to catalyse the isomerization reaction (Table
1
3b
enol ethers.
Despite these achievements, the scope of
sulfenylated ketones and the accomplished enantioselectivities
should be further improved. In addition, in order to reach more
sustainable processes, new methodologies with a high atom
economy are desired.
1
). Among them, the most electrondeficient (S)-
DIFLUOROPHOS provided the highest enantioselectivity (88:12
er). With the ligand of choice, we optimized reaction conditions
(
Table 2). It was found that the simple inorganic salt RhCl
performed better than [Rh(COD)]BF or [Cp*RhCl (entries 1-3).
Interestingly, anhydrous RhCl provided very low conversion
entry 4). This observation suggests that water could have an
3 2
.H O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Our group reported a greener strategy to prepare racemic α-
2 2
]
4
sulfenylated
ketones,
consisting
in
the
tandem
3
hydrothiolation/isomerization of propargylic alcohols, via
(
1
4
sulfenylated allylic alcohols as intermediates. In one of these
studies, Pd(OAc) was found to be an efficient catalyst for the
important role in mediating a proton-transfer process. Therefore,
we studied the water effect on the reaction performance. It was
observed that our system can operate in the presence of small
amounts of water, although the catalytic performance didn’t
improve by increasing water concentration (see Supporting
Information).
2
14d
hydrothiolation of primary propargylic alcohols. By using the
same conditions, we have been able to synthesize a range of
racemic sulfenylated secondary allylic alcohols. We hypothesized
that in the presence of a chiral catalyst, these could isomerize to
provide chiral α-sulfenylated ketones (Scheme 1c). Only very
recently, Zhao has reported the Rh-catalyzed isomerization of
racemic allylic, homoallylic and bishomoallylic secondary alcohols
to produce ketones with α-, β-, and γ-tertiary stereocenters,
Table 2. Optimization of the asymmetric
a
isomerization of secondary alcohol 1a
O
1
5,16
OH
[Rh]/(S)-
DIFLUOROPHOS
respectively.
Inspired by this pioneering work, we were able to
.H O and the
find a catalytic system, composed by RhCl
3
2
Ph
Ph
2a
Tol / 55 (°C) / 36 h
S
commercially available ligand (S)-DIFLUORPHOS, which can
enantioselectively promote the redox-isomerization of allylic
alcohols containing a sulphide group. Thus, we report here a two-
step procedure to prepare enantiopure α-sulfenylated ketones,
which overcomes the problem of low-atom economy of the existing
methodologies (Scheme 1c).
1a
S
Entry
[Rh]
solvent
%
yield
er c
b
Table 1. Ligand screening for the asymmetric Rh-
1
[Rh(COD)]BF4
[Cp*RhCl
Tol
Tol
43%
75%
96%
28%
93%
98%
89%
71:29
50:50
88:12
-
a
catalyzed isomerization of 1a.
2
3
4
5
6
7
2 2
]
OH
O
RhCl .H O
Tol
3
2
RhCl3.H2O (2.5 mol%)
L* (7.5 mol%)
Tol / 55 (°C) / 36 h
Ph
Ph
2a
RhCl3
Tol
*
S
1
a
S
RhCl
3 2
.H O
THF
hexane
73:27
88:12
88:12
RhCl
3
.H
2
O
O
RhCl
3
.H
2
cylohe
xane
PPh2
PPh2
PTol2
PTol2
OMe
PPh2
8d
9e
10f
RhCl
RhCl
RhCl
RhCl
RhCl
RhCl
Tol
Tol
Tol
Tol
Tol
Tol
53%
28%
82%
97%
95%
90%
86:14
-
3
2
.H O
2
.H O
2
.H O
2
.H O
2
.H O
2
.H O
3
3
3
3
3
(
7
R)-BINAP
9% yield
19:81 er
(R)-MOP
38% yield
46:54 er
(R)-Tol-BINAP
88:12
50:50
87:13
85:15
0% yield
1
1g
12h
F
F
O
O
O
F
F
O
O
O
O
PPh2
PPh2
(
DBTMPh)2
O
O
3 i
PPh2
PPh2
1
(DBTMPh)2
a[Rh]-precursor (2.5 mol%), (S)-DIFLUORPHOS (7.5 mol%),
O
O
O
b
1
a (0.2 M). NMR yields using 1,3,5-trimethoxybenzene as
(
S)-DIFLUOROPHOS
0% yield
(
R)-DTBM-SEGPHOS
(R)-SEGPHOS
82% yield
24:76 er
c
d
internal-standard. Determined by HPLC. AgBF
Reaction performed at 0.1 M of 1a. Reaction performed at 0.4
M of 1a. Reaction performed at RT. Reaction performed at
0 °C. Reaction performed at 90 °C.
4
was added.
9
83% yield
e
f
88:12 er
35:65 er
g
h
i
8
Ph2P
PCy2
P
Fe
Fe
Enantioselectivities were higher in apolar solvents, hence,
P
toluene, hexane and cyclohexane provided similar values (entries
, 6-7). Nevertheless, we chose toluene since is considered a more
3
JOSiPHOS SL-J004-2
% yield
(R,R)-Et-Ferrocelane
1
7
benign solvent. The addition of both organic and inorganic bases
inhibited the reaction completely, which was unexpected since
many methodologies for the metal-catalyzed isomerization of
allylic alcohols require the use of catalytic amounts of base (see
0
0% yield
aRhCl
3
(
2.5 mol%), ligand (7.5 mol%), 1a (0.2 M); NMR yields
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The Journal of Organic Chemistry
1
5f,16,18
Supporting Information).
non-coordinating BF
4
Exchange of chlorine atoms by
didn’t improve the catalytic performance
(entry 8). Variations on the concentration didn’t show any increase
Table 3. Scope of the Rh-catalyzed isomerization of secondary allylic alcohols.
on the enantioselectivity either (entries 9-10). Finally, we observed
that
-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
OH
RhCl .H O (2.5 mol%)
O
3
2
(
S)-DIFLUOROPHOS (7.5 mol%)
Ph
Ph
Tol / 55 (°C) / 36 h
S
S
1
2
Entry
Ketone
% yieldb
erc
Entry
Ketone
% yieldb
erc
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
Ph
Ph
2i
15d
1
90
88:12
9
-
S
S
2
a
m-Me-C6H4
p-NO2-C6H4
O
O
Ph
Ph
2j
2
3
71
79
82
71
>99:1
88:12
10
11
75
75:25
84:16
60:40
83.5:16.5
85:15
85:15
-
S
S
2b
Ph
o-Me-C6H4
O
O
Ph
Ph
Ph
88
S
S
S
S
2c
p-Me-C6H4
2k
Cy
O
O
4
5
6
7
8
88:12
12
13
14
15
16
92
S
t
2d
p- Bu-C6H4
2l
Ph
O
O
Ph
p-Me-C6H4
87.5:12.5
87:13
80
S
S
i
2
e
p- Pr-C6H4
2m
Ph
Ph
O
O
Ph
2f
o-Me-C6H4
85
70
86
74
57
S
p-OMe-C6H4
p-Br-C6H4
2n
O
O
Ph
Ph
82:18
S
S
S
2g
2o
Ph
O
O
Py
82:18
No reaction
S
S
2
h
p-F-C6H4
2p
Ph
a[Rh]-precursor (2.5 mol%), (S)-DIFLUOROPHOS (7.5 mol%), 1a (0.2 M). Isolated yields. Determined by HPLC. NMR yield
b
c
d
using 1,3,5-trimethoxybenzene as internal-standard.
by lowering the temperature, the enantioselectivity was completely
lost (entry 11), while it remained the same at high temperatures
entry 12). A slight loss in the enantioselectivity was observed at
reaction conditions (Table 3). All compounds were easily obtained
through the regioselective hydrothiolation of propargylic alcohols
catalyzed by Pd(OAc)
thioether moiety exclusively at the β-position of the alcohol (see
Supporting information).
different substituents on the aryl of the thioether moiety were
isomerized in high yields and good to high enantioselectivities
(substrates 2a-2h). We were pleased to see that ketone 2b, bearing
a thiophenyl moiety, was obtained with perfect enantiopurity
(>99:1 er). As far as we know, this is the highest enantioselectivity
obtained for the isomerization of racemic allylic secondary
alcohols. The reaction tolerated the presence of alkyl groups in
para-position and also the more electron donating methoxy group
(substrates 2c-2f), maintaining good enantioselectivities (~88:12
(
9
2
, which allows the introduction of a
0 C° (entry 13). This suggests that two competing pathways might
14d,19
operate, where only one is enantioselective. The desired
enantioselective pathway requires thermal activation, while the
competing non-enantioselective pathway operates at room
temperature. We have shown in our previous reports that Lewis
acidic Au(I) and Cu(I) species are able to promote a 1,2-H-shift on
sulfenylated allylic alcohols. Therefore, traces of free Rh(III)
species could be the responsible of the competing non-
enantioselective isomerization.
A range of substrates bearing
1
4
16
To study the scope of the reaction, different secondary allylic
alcohols were subjected to isomerization under the optimized
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er). The presence of halogen groups slightly lowered the
formed. Subsequent β-hydride elimination leads to the enone-Rh-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
enantioselectivity (substrates 2g-2h). The introduction of an
electron withdrawing nitro group on the arylthioether moiety
resulted in almost no conversion to ketone 2i. Allylic alcohol with
hydride intermediate C, where the chirality of the starting material
would be lost, enabling a steroconvergent process. Next, this
intermediate undergoes 1,2-insertion, leading to D, which will form
the enolate F through tautomerization on specie E. Finally,
enantioselective protonation of the enolate provides the chiral
ketone and catalyst regeneration.
a
non-aromatic cyclohexyl thioether group, generated the
corresponding ketone with similar enantioselectivity (2k).
Similarly, when the aromatic ring next to the carbonyl was
changed by
enantioselectivity (2l). On the other hand, we could obtain ketones
m and 2n, having an o-, or p-methyl group on the phenyl group,
a
methyl group, the reaction showed poor
To support the proposed reaction mechanism, we performed
deuterium labelling experiments shown in Scheme 2. Isomerization
of deuterated substrate 1b-D under the optimized conditions
(Scheme 2a), showed 38% of deuterium incorporation in both, α-,
and β-positions of the ketone (2:3). When non-deuterated allylic
alcohol 1b was isomerized in presence of deuterium oxide, the
ketone with the same deuterium distribution (2:3) was obtained,
albeit with 92% of deuterium content (Scheme 2b). Both
experiments show a proton-deuterium scrambling between α-, and
2
with good enantiomeric ratios. The phenyl ring could be also
changed for a thiophene, keeping a good level of enantioselectivity
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(2o). Finally, the presence of a pyridine ring completely inhibited
the reaction, probably due to coordination of the nitrogen atom to
the metal centre (2p). It should be noted that the current
methodology only allows the formation of ketones with a methyl
next to the C-thioether moiety. This is because the Pd-catalyzed
hydrothiolation reaction used for the preparation of allylic alcohols,
is limited to terminal alkynes due to reactivity and regioselectivity
issues. We have therefore only studied the scope of terminal
secondary allylic alcohols.
3
β-positions. Since hydrated RhCl is used, an exchange between the
hydride and water present on the system could originate the H/D
scrambling (Figure 2, species C and C’). To corroborate this
hypothesis, water was added in the isomerization of deuterated
alcohol 1b-D (Scheme 2c). No deuterium was incorporated in the
final product. In addition, we observed a loss of enantioselectivity
when deuterium oxide was added in the reaction mixture (Scheme
P
RhCl3.H2O +
*
P
23
2
b). This suggests that water could participate in the protonation
Ar'
S
Cl
Rh
Cl
of the enolate, which should be the enantio-determining step.
Therefore, water has an important role, as suggested during the
optimization of reaction conditions (see Table 2, entry 4 vs 3). In
summary, deuterium experiments support a mechanism involving
a Rh-hydride-enone intermediate. However, all attempts for
trapping any reaction intermediate failed.
P
P
O
SAr'
Ar
O
H
Ar
A'
Cl
P
Ar
+
H
*
Rh
P
A
HCl
SAr'
O
Cl
OH
H
SAr'
H
Ar
H2O
or
HCl
P
P
Ar
Rh
SAr'
Cl
O
SAr'
B
H
P
P
Scheme 2. Deuterium experiments
Rh
Cl
Ar
O
F
(96 %)
(40%)
D
SAr'
Ar
OH
O
O
H
Rh
Cl
D
(60%)
D
P
P
Standard Conditions
92% Conv.
+
Ph
a)
Ph
1b-D
Ph
2b
SAr'
Ar
S
99% ee
S
S
H
O
-
D1
Ph 2b-D2
Ph
Ph
P
P
Rh
Cl -O
C
HHO H O (From RhCl .H O)
2
3
2
38% D
SAr'
Ar
E
H
SAr'
Ar
O
(40%)
D
O
O
P
OH
Standard Conditions
D2O (4.4 eq)
70% Conv.
D
S
Rh
P
H
Rh
Cl
H
(60%)
P
P
b)
Ph
Ph
+
Ph
D
+
Ph
2b-D3
D
Cl
O
O
1b
S
S
S
D
70% ee
2b-D1
2b
Ph
Ph
Ph
Ph
-D2
Ph
C'
92% D
Figure 2. Proposed catalytic cycle for the Rh-catalyzed
isomerization of secondary allylic alcohols.
(96 %)
OH
Standard Conditions
H2O (4.4 eq)
O
Ph
D
c) Ph
b-D
0% D
53% Conv.
S
S
1
2b
Ph
Three different mechanisms have been proposed for the metal-
catalyzed isomerization of allylic alcohols, all of them involving
In conclusion, we have shown that the asymmetric
isomerization of allylic alcohols can be used to obtain chiral α-
sulfenylated ketones, which are highly versatile building blocks.
The starting allylic alcohols can easily be prepared from readily
2
0
metal-hydride species. The first one, involving alkylmetal
intermediates, requires the use of a metal-hydride complex as a
2
1
catalyst, either isolated or generated in situ. The second
mechanism proceeds through π-allyl intermediates and it has been
usually proposed for low valent metals that can undergo an
oxidative addition/reductive elimination sequence.20 The last one,
proposed by Trost, involves a coordinated enone as a key
2
available propargylic alcohols and thiols in presence of Pd(OAc) .
Although good enantioselectivties could be obtained in some cases
(typically 87:13 er and >99:1 for substrate 1b), the system is
limited to allylic alcohols containing arylthioether groups and aryl
ketones. We hope that this report will inspire researchers to further
develop benign methodologies to prepare enantioenriched α-
sulfenylated carbonyl compounds.
2
2
intermediate. This mechanism was also supported by Gimeno,
1
8
Sordo and co-workers with theoretical calculations. Among all
mechanistic proposals, this is the only one that assigns a role on the
oxygen atom of the allylic alcohol. As suggested by Zhao and co-
workers, our catalyst would follow a similar mechanism as the one
16a
proposed by Trost (Figure 2). First, coordination of the substrate
EXPERIMENTAL SECTION
followed by HCl formation would generate alkoxide intermediate
B. It should be noted that the substrates used in this study contain a
thioether group, which is known to be a good ligand for transition
metals. Consequently, off-cycle species resembling to A’ might be
General information. All commercially available
reagents were purchase from Sigma-Aldrich Company and
ACS Paragon Plus Environment

Page 5 of 10
The Journal of Organic Chemistry
1
used as received without any purification. Solvents were
acetate / petroleum ether); H NMR (400 MHz, CDCl
3
): δ =
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
obtained from VAC purification system and nitromethane was
purchased in anhydrous grade from Sigma Adrich. Chiral
phosphine ligands were purchased from Aldrich or Strem.
Rhodium(III) chloride hydrate was purchased in Apollo
Scientific. All reactions were carried out using standard
Schlenk techniques under an atmosphere of argon with oven-
dried glassware. Analytical thin-layer chromatography (TLC)
was conducted using Merck analyticl TLC plates (silica gel 60
F-254). Compounds were visualized by ultraviolet light. Flash
column chromatography was performed on silica gel (35-70
micron). Proton and carbon nuclear magnetic resonance
7.45 – 7.33 (m, 7H), 7.18 – 7.15 (m, 2H), 5.55 (d, J = 1.2 Hz, 1H),
1
3
1
5.30 (bs, 1H), 5.07 (d, J = 0.6 Hz, 1H), 2.37 (s, 3H); C{ H} NMR
(101 MHz, Toluene-d ): δ = 149.7, 141.9, 137.6, 133.5, 129.9, 129.6,
8
128.0, 126.8, 112.5, 76.0, 20.6 ppm; HRMS (ESI-TOF) m/z: [M +
+
Na] Calcd for C16
H16OSNa 279.0814; Found 279.0802.
2-((4-(tert-Butyl)phenyl)thio)-1-phenylprop-2-en-1-ol (1d):
yellowish oil (89 mg, 30% yield), (SiO
(v/v) ethyl acetate / petroleum ether); H NMR (400 MHz,
2
-chromathography, 10%
1
Toluene-d
8
): δ = 7.40 – 7.37 (m, 2H), 7.35 – 7.31 (m, 2H), 7.20 –
7.16 (m, 2H), 7.12 – 7.09 (m, 3H), 5.56 (d, J = 1.2 Hz, 1H), 5.19 –
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
5.06 (m, 2H), 1.76 (d, J = 4.1 Hz, 1H), 1.17 (s, 9H) ppm; C{ H}
NMR (101 MHz, Toluene-d ): δ = 150.7, 149.3, 141.9, 133.1, 129.7,
(
NMR) spectra were obtained using a Bruker 400 MHz
8
spectrometer. Chemical shifts were recorded as δ values in
ppm. Coupling constants (J) are given in Hz. High resolution
mass spectrometry was recorded on Bruker Daltonics
MicrOTOF. Chiral separation was performed with HPLC (YL-
Clarity HPLC instrument) using Daicel Chiralcel columns AD
and OJ-H. Optical rotations were recorded in a Perkin-Elmer
128.1, 126.8, 126.2, 113.1, 76.0, 34.2, 30.8 ppm; HRMS (ESI-TOF)
+
m/z: [M + Na] Calcd for C19
H22OSNa 321.1284; Found 321.1287.
2-((4-Isopropylphenyl)thio)-1-phenylprop-2-en-1-ol
(1e):
yellowish oil (153 mg, 54% yield), (SiO
(v/v) ethyl acetate / petroleum ether); H NMR (400 MHz,
2
-chromathography, 10%
1
3
CDCl ): δ = 7.43 (m, 2H), 7.41 – 7.33 (m, 5H), 7.20 (d, J = 8.1 Hz,
2
41 Polarimeter. The absolute configuration of the obtained
2H), 5.57 (d, J = 1.2 Hz, 1H), 5.30 (s, 1H), 5.11 (d, J = 0.6 Hz, 1H),
1
3
1
chiral ketones was assigned by comparison of the chiral HPLC
2.91 (m, 1H), 1.27 (d, J = 6.9 Hz, 6H) ppm; C{ H} NMR (101
MHz, CDCl ): δ = 149.2, 148.8, 141.1, 133.5, 129.1, 128.4, 128.0,
127.4, 126.7, 114.1, 76.2, 33.8, 23.8 ppm; HRMS (ESI-TOF) m/z:
trace and optical rotation of compound 2b with the reported
3
13b
in the literature. Non-commercially available propargylic
24
+
alcohols were prepared as reported in the literature. Yields
[M + Na] Calcd for C18
H20OSNa 307.1127; Found 307.1124.
for allylic alcohols 1a-1p were from low to moderate since they
decomposed during the purification in silica.
2-((4-Methoxyphenyl)thio)-1-phenylprop-2-en-1-ol
(1f):
colorless solid (208 mg, 76%, yield), (SiO
15% (v/v) ethyl acetate / petroleum ether); H NMR (400 MHz,
2
-chromathography,
1
Toluene-d
8
): δ = 7.46 – 7.44 (m, 2H), 7.41 – 7.32 (m, 5H), 6.91 –
6
.88 (m, 2H), 5.46 (d, J = 1.1 Hz, 1H), 5.31 (d, J = 4.1 Hz, 1H), 4.92
Experimental procedures for the synthesis of allylic
alcohols 1a-1p and their spectroscopic data. Pd(OAc)2 (4.5
mg, 2 mol%) was weighed and transferred to a 5 mL
microwave vial containing a small magnet. The vial was
capped tightly and 2.0 mL of dry toluene (compounds 1a-1j,
(
d, J = 0.5 Hz, 1H), 3.84 (s, 3H), 2.33 (d, J = 4.3 Hz, 1H) ppm;
C{ H} NMR (101 MHz, Toluene-d
1
3
1
8
): δ = 160.1, 150.0, 141.1, 136.0,
1
28.4, 128.1, 126.7, 122.3, 114.9, 111.8, 76.2 ppm; HRMS (ESI-TOF)
+
m/z: [M + Na] Calcd for C16
16
H O
2
SNa 295.0763; Found
2
1o-1p) or nitromethane (compounds 1j-1n) followed by the
(1g):
corresponding propargylic alcohol (1 mmol) were added and
stirred at room temperature for 5 minutes. The desired thiol
2
-chromathography,
1
(
8
(
1.1 mmol) was added and the reaction mixture was heated at
0 °C (oil bath) for 16 h (compounds 1a,1c-1i, 1l-1n), at 80 °C
oil bath) for 48 h (compounds 1k, 1p) or at 55 °C (oil bath) for
8
Toluene-d ): δ = 7.47 – 7.44 (m, 2H), 7.42 – 7.34 (m, 5H), 7.29
– 7.26 (m, 2H), 5.70 (d, J = 1.2 Hz, 1H), 5.28 (bs, 1H), 5.22 (d, J =
1
3
1
0
.6 Hz, 1H), 2.30 (bs, 1H) ppm; C{ H} NMR (101 MHz,
16 h (compounds 1b, 1j, 10). After completion of the reaction
toluene was evaporated under reduced pressure and the
residue was purified by silica-gel column chromatography to
afford the desired product.
Toluene-d
8
): δ = 147.4, 140.8, 134.2, 132.4, 132.1, 128.5, 128.2,
+
1
26.7, 122.1, 116.2, 76.2 ppm; HRMS (ESI-TOF) m/z: [M + Na]
Calcd for C15 13BrOSNa 342.9763; Found 342.9733.
-((4-Fluorophenyl)thio)-1-phenylprop-2-en-1-ol
H
2
(1h):
1
-Phenyl-2-(m-tolylthio)prop-2-en-1-ol (1a): yellow oil, (167
colorless solid (121 mg, 46% yield), (SiO2-chromathography,
mg, 65% yield), (SiO2-chromathography, 10% (v/v) ethyl
1
1
10% (v/v) ethyl acetate / petroleum ether); H NMR (400 MHz,
acetate / petroleum ether); H NMR (400 MHz, CDCl
.46 – 7.33 (m, 5H), 7.26 – 7.24 (m, 3H), 7.15 – 7.12 (m, 1H), 5.63
d, J = 1.2 Hz, 1H), 5.30 (d, J = 4.0 Hz, 1H), 2.45 (d, J = 4.4 Hz,
3
): δ =
3
CDCl ): δ = 7.44 – 7.32 (m, 7H), 7.07 – 7.03 (m, 2H), 5.59 (d, J =
7
(
1
.2 Hz, 1H), 5.30 (b, 1H), 5.04 (s, 1H), 2.33 (d, J = 3.7 Hz, 1H)
1
3
1
1
13
1
3 C-F
ppm; C{ H} NMR (101 MHz, CDCl ): δ = 162.8 (d, J = 248.7
1
1
H), 2.36 (s, 3H) ppm; C{ H} NMR (101 MHz, CDCl
41.1, 139.1, 133.6, 132.4, 130.0, 129.1, 128.8, 128.4, 128.1, 126.7, 115.1,
76.2, 21.2 ppm; HRMS (ESI-TOF) m/z: [M + Na] Calcd for
16OSNa 279.0814; Found 279.0809.
1-Phenyl-2-(m-phenylthio)prop-2-en-1-ol (1b) : yellowish
oil, (146 mg, 60% yield), (SiO2-chromathography, 10% (v/v)
3
): δ = 148.2,
3
Hz), 148.8, 140.9, 135.7 (d, JC-F = 8.3 Hz), 128.5, 128.2, 127.4 (d,
4
2
+
JC-F = 3.3 Hz), 126.7, 116.5 (d, J = 22.0 Hz), 113.8, 76.3 ppm;
C-F
+
HRMS (ESI-TOF) m/z: [M + Na] Calcd for C15
H13FOSNa
16
C H
2
5
283.0563; Found 283.0559.
2
-((4-Nitrophenyl)thio)-1-phenylprop-2-en-1-ol (1i): yellow
1
oil (155 mg, 54% yield), (SiO -chromathography, 20% (v/v)
ethyl acetate / petroleum ether); H NMR (400 MHz, CDCl
3
):
2
1
ethyl acetate / petroleum ether); H NMR (400 MHz, CDCl
3
):
δ = 7.45 – 7.32 (m, 9H), 5.65 (d, J = 1.2 Hz, 1H), 5.30 (d, J = 4.0
Hz, 1H), 5.17 (d, J = 0.6 Hz, 1H), 2.39 (d, J = 4.3 Hz, 1H) ppm;
δ = 8.08 (d, J = 9.0 Hz, 2H), 7.39 – 7.29 (m, 7H), 6.13 (d, J = 1.3
13
1
1
3
1
Hz, 1H), 5.69 (d, J = 0.8 Hz, 1H), 5.25 (s, 1H) ppm; C{ H} NMR
101 MHz, CDCl ): δ = 144.9, 143.5, 140.5, 137.0, 128.9, 128.6,
3
C{ H} NMR (101 MHz, CDCl ): δ = 148.0, 140.9, 133.0, 132.5,
(
3
1
29.3, 128.5, 128.2, 128.0, 126.7, 115.2, 76.1 ppm; HRMS (ESI-TOF)
+
128.5, 126.7, 124.0, 123.9, 76.6, 30.9 ppm; HRMS (ESI-TOF) m/z:
[M + Na] Calcd for C15
m/z: [M + Na] Calcd for C15
H14OSNa 265.0658; Found
+
H13NO
3
SNa 287.0616; Found 287,0627.
2
65.0666.
-Phenyl-2-(p-tolylthio)prop-2-en-1-ol (1c): yellowish oil,
139 mg, 52% yield), (SiO -chromathography, 10% (v/v) ethyl
1-Phenyl-2-(o-tolylthio)prop-2-en-1-ol (1j): yellow oil (111
1
1
mg, 43% yield); H NMR (400 MHz, CDCl
3
): δ = 7.47 – 7.44 (m,
(
2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 10
3
H), 7.43 – 7.33 (m, 3H), 7.30 – 7.25 (m, 2H), 7.24 – 7.18 (m, 1H),
General procedure for the isomerization of allylic
alcohols 1a-p and characterization data for ketones 2a-p.
RhCl .H O (0.52 mg, 2.5 mol%) and (S)-DIFLUORPHOS (5.12
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5.51 (d, J = 1.2 Hz, 1H), 5.32 (s, 1H), 4.78 (d, J = 0.5 Hz, 1H), 2.31
(s, 3H) ppm; C{ H} NMR (101 MHz, CDCl
141.1, 135.0, 130.8, 128.9, 128.4, 128.2, 127.4, 126.8, 126.6, 111.7,
7
1
3
1
3
): δ = 147.7, 141.7,
3
2
mg, 7.4 mol%) were weighed and transferred to a 5 mL
microwave vial containing a small magnet. The vial was
capped tightly and 0.25 mL of dry toluene solvent was added
and stirred at room temperature for 15 minutes. Next, a
solution of the allylic alcohol (0.1 mmol) in toluene (0.25 mL)
was added and the reaction mixture was heated at 55 °C (oil
bath) for 36 h. After completion of the reaction, the reaction
mixture was filtered through a plug of silica washed with
EtOAc. The crude was evaporated under reduced pressure and
the residue was purified by silica-gel column chromatography
to afford the desired ketone.
+
6.3, 20.4 ppm; HRMS (ESI-TOF) m/z: [M + Na] Calcd for
C
16
H
2
16OSNa 279.0814; Found 279.0810.
-(Cyclohexylthio)-1-phenylprop-2-en-1-ol (1k): yellow oil
(
116 mg, 47% yield), (SiO
2
-chromathography, 10% (v/v) ethyl
1
acetate / petroleum ether); H NMR (400 MHz, CDCl
3
): δ =
7
.46 – 7.29 (m, 5H), 5.60 (d, J = 1.1 Hz, 1H), 5.27 (d, J = 5.1 Hz,
1
1
(
H), 5.19 (s, 1H), 2.97 – 2.91 (m, 1H), 2.46 – 2.44 (m, 1H), 2.03 –
.97 (m, 2H), 1.80 – 1.73 (m, 2H), 1.64 – 1.59 (m, 1H), 1.39 – 1.23
m, 5H) ppm; C{ H} NMR (101 MHz, CDCl ): δ = 146.8, 141.3,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
128.3, 127.9, 126.5, 112.2, 77.1, 44.3, 32.9 (x2), 26.0 (x2), 25.8 ppm;
HRMS (ESI-TOF) m/z: [M + Na] Calcd for C15
271.1127; Found 271.1111.
+
H20OSNa
1-Phenyl-2-(m-tolylthio)propan-1-one (2a): yellowish oil (23
mg, 90% yield), (SiO
acetate / petroleum ether); H NMR (400 MHz, CDCl
2
-chromathography, 5% (v/v) ethyl
1
3
-(Phenylthio)but-3-en-2-ol (1l): yellow oil (92 mg, 51%
3
): δ =
yield), (SiO
petroleum ether); H NMR (400 MHz, C
2
-chromathography, 10% (v/v) ethyl acetate /
7.97 (dd, J = 8.4, 1.6 Hz, 2H), 7.60 – 7.56 (m, 1H), 7.49 – 7.45
(m, 2H), 7.20 – 7.17 (m, 3H), 7.15 – 7.11 (m, 1H), 4.65 (q, J = 6.8
1
6
D
6
): δ = 7.33 (dd, J =
1
3
1
8.1, 1.4 Hz, 1H), 7.11 (m, 2H), 6.95 – 6.88 (m, 2H), 5.34 (d, J = 1.2
Hz, 1H), 4.94 (d, J = 0.6 Hz, 1H), 4.08 (d, J = 6.6 Hz, 1H), 1.24
Hz, 1H), 2.32 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H) ppm; C{ H} NMR
(101 MHz, CDCl ): δ = 196.4, 138.7, 135.9, 135.0, 133.0, 131.7, 131.3,
3
1
3
1
(
d, J = 6.4 Hz, 3H) ppm; C{ H} NMR (101 MHz, C
6
D
6
): δ =
129.4, 128.7, 128.6, 128.5, 46.5, 21.2, 17.1 ppm; HRMS (ESI-TOF)
+
1
50.4, 133.3, 132.7, 129.1, 112.5, 69.9, 22.8 ppm; HRMS (ESI-TOF)
m/z: [M + Na] Calcd for C16
H16OSNa 279.0814; Found
+
+
m/z: [M] Calcd for C10
H
12O 180,0609; Found 180,0672.
279.0810; HPLC analysis: Daicel Chiralcel OJ-H column, n-
Hexane: isopropanol = 90:10, flow rate 1 mL/min, λ = 254 nm
(channel 1), 232 nm (channel 2): t (major) = 10.2 min, t
1 2
2-(Phenylthio)-1-(p-tolyl)prop-2-en-1-ol (1m): yellow oil (98
mg, 38% yield), (SiO
acetate / petroleum ether); H NMR (400 MHz, CDCl
2
-chromathography, 10% (v/v) ethyl
1
3
): δ =
(minor) = 19.6 min; 76% ee.
7
.45 – 7.42 (m, 2H), 7.37 – 7.31 (m, 5H), 7.21 – 7.19 (m, 2H), 5.64
(R)-1-Phenyl-2-(penyllthio)propan-1-one (2b)13b: yellowish
(
d, J = 1.2 Hz, 1H), 5.26 (d, J = 4.2 Hz, 1H), 5.16 (d, J = 0.7 Hz,
oil (17 mg, 71% yield), (SiO
acetate / petroleum ether); H NMR (400 MHz, CDCl
2
-chromathography, 5% (v/v) ethyl
1
3
1
1
1
H), 2.38 (s, 3H), 2.28 (d, J = 4.4 Hz, 1H) ppm; C{ H} NMR (101
MHz, C ): δ = 148.3, 138.2, 138.0, 133.1, 132.9, 129.4, 129.3,
28.0, 126.8, 115.0, 76.1, 21.3 ppm; HRMS (ESI-TOF) m/z: [M +
3
): δ =
6
D
6
8.02 – 7.89 (m, 2H), 7.65 – 7.56 (m, 1H), 7.48 (dd, J = 8.3, 6.9
Hz, 2H), 7.41 – 7.29 (m, 5H), 4.66 (q, J = 6.9 Hz, 1H), 1.55 (d, J
1
+
13
1
Na] Calcd for C16
-(Phenylthio)-1-(o-tolyl)prop-2-en-1-ol (1n): yellow oil (80
mg, 32% yield), (SiO -chromathography, 10% (v/v) ethyl
acetate / petroleum ether); H NMR (400 MHz, CDCl
7.53 (dd, J = 2.4 Hz, 6.8 Hz 1H), 7.46 (m, 2H), 7.38 – 7.32 (m,
3H), 7.27 – 7.22 (m, 2H), 7.16 (m, 1H), 5.48 (d, J = 1.3 Hz, 1H),
H16OSNa 279.0814; Found 279.0806.
3
= 6.9 Hz, 3H) ppm; C{ H} NMR (101 MHz, CDCl ): δ = 196.3,
2
135.6, 134.8, 133.2, 131.5, 129.0, 128.7, 128.6, 46.1, 17.0 ppm; HRMS
+
2
(ESI-TOF) m/z: [M + Na] Calcd for C15
H
14OSNa 265.0658;
1
24
3
): δ =
Found 265.0654; [α]
D
= +48.3 (c = 1.000, CHCl
3
); HPLC
analysis: Daicel Chiralcel OJ-H column, n-Hexane:
isopropanol = 98:2, flow rate 1 mL/min, λ = 254 nm (channel
1), 232 nm (channel 2): t (major) = 29.1 min, t (minor) = 59.2
1 2
min; >99% ee (R).
5.45 (d, J = 3.9 Hz, 1H), 5.20 (d, J = 0.8 Hz, 1H), 2.30 (bs, 1H),
.28 (s, 3H) ppm; 13C{ H} NMR (101 MHz, CDCl
1
2
3
): δ = 147.4,
1
1
38.7, 136.0, 133.2, 132.5, 130.4, 129.2, 128.1, 128.0, 126.4, 126.2,
15.5, 72.6, 19.1 ppm; HRMS (ESI-TOF) m/z: [M + Na] Calcd
1-Phenyl-2-(p-tolylthio)propan-1-one (2c): yellowish oil (20
+
mg, 79% yield), (SiO
acetate / petroleum ether); H NMR (400 MHz, CDCl
2
-chromathography, 5% (v/v) ethyl
1
for C16
H
16OSNa 279.0814; Found 279.0827.
3
): 8.00 –
2
-(Phenylthio)-1-(thiophen-3-yl)prop-2-en-1-ol (1o): yellow
7.97 (m, 2H), 7.61 – 7.56 (m, 1H), 7.50 – 7.46 (m, 2H), 7.26 (d, J
= 8.1 Hz, 2H), 7.11 (d, J = 8.6 Hz, 2H) 4.58 (q, J = 6.8 Hz, 1H),
oil (90 mg, 36% yield), (SiO
ethyl acetate / petroleum ether); H NMR (400 MHz, Toluene-
d
5
0.6 Hz, 1H) ppm; C{ H} NMR (101 MHz, Toluene-d
148.4, 143.2, 133.3, 132.8, 129.0, 127.5, 126.2, 125.3, 122.0, 114.0, 72.4
ppm; HRMS (ESI-TOF) m/z: [M + Na] Calcd for C13
2
2
-chromathography, 10% (v/v)
1
13
1
2.35 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H); C{ H} NMR (101 MHz,
CDCl ): 196.1, 139.0, 135.8, 135.2, 133.0, 129.7, 128.7, 128.5, 127.7,
46.2, 21.2, 16.8; HRMS (ESI-TOF) m/z: [M + Na] Calcd for
16OSNa 279.0814; Found 279.0804; HPLC analysis: Daicel
Chiralcel AD column: n-Hexane: isopropanol = 98:2, flow rate
1 mL/min, λ = 254 nm (channel 1), 232 nm (channel 2): t
(major) = 8.4 min, t (minor) = 9.1 min; 76% ee.
2-((4-(tert-Butyl)phenyl)thio)-1-phenylpropan-1-one (2d):
8
): δ = 7.32 – 7.29 (m, 2H), 7.01 – 7.69 (m, 5H), 6.85 (dd, J =
3
+
.0, 3.0 Hz, 1H), 5.52 (d, J = 1.2 Hz, 1H), 5.08 (s, 1H), 5.07 (d, J =
1
3
1
8
): δ =
16
C H
+
H12OS
2
Na
1
71.0222; Found 271.0216.
-(Phenylthio)-1-(pyridin-3-yl)prop-2-en-1-ol (1p): yellow oil
2
2
(
142 mg, 58% yield), (Al
2
O
3
-chromathography, 99% (v/v) ethyl
yellowish oil (24 mg, 82% yield), (SiO
(v/v) ethyl acetate / petroleum ether); H NMR (400 MHz,
2
-chromathography, 5%
1
1
acetate / triethylamine); H NMR (400 MHz, CDCl
3
): δ = 8.60
(
m, 1H), 8.52 (dd, J = 4.9, 1.6 Hz, 1H), 7.81 (dt, J = 7.9, 1.8 Hz,
3
CDCl ): δ = 7.96 (dd, J = 8.0, 1.2 Hz, 2H), 7.60 – 7.55 (m, 1H),
1
1
H), 7.38 – 7.36 (m, 2H), 7.34 – 7.28 (m, 4H), 5.65 (d, J = 1.1 Hz,
7.48 – 7.44 (m, 2H), 7.30 (s, 4H), 4.61 (q, J = 6.8 Hz, 1H), 1.55
13
1
13
1
H), 5.31 (s, 1H), 5.18 (s, 1H), 2.49 (bs, 1H) ppm; C{ H} NMR
101 MHz, CDCl ): δ = 148.4, 147.8, 147.4, 134.9, 133.0, 129.4,
28.3, 123.6, 115.7, 73.9 ppm; HRMS (ESI-TOF) m/z: [M + Na]
Calcd for C14 13NOSNa 243.0718; Found 243.0727.
(d, J = 6.8 Hz, 3H), 1.32 (s, 9H) ppm; C{ H} NMR (101 MHz,
CDCl ): δ = 196.5, 152.0, 135.8, 134.7, 133.0, 128.7, 128.5, 128.0,
(
1
3
3
+
126.00, 46.2, 34.7, 31.2, 16.9 ppm; HRMS (ESI-TOF) m/z: [M +
+
H
Na] Calcd for C19
H22OSNa 321.1284; Found 321.1286; HPLC
analysis using: Daicel Chiralcel OJ-H column, n-Hexane:
isopropanol = 99.5:0.5, flow rate 1 mL/min, λ = 254 nm
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The Journal of Organic Chemistry
(
channel 1), 232 nm (channel 2): t
1
(major) = 13.2 min, t
2
279.0814; Found 279.0810; HPLC analysis: Daicel Chiralcel AD
column, n-Hexane: isopropanol = 95:5, flow rate 1 mL/min, λ
= 254 nm (channel 1), 232 nm (channel 2): t (major) = 6.2 min,
(minor) = 6.9 min; 50% ee.
2-(Cyclohexylthio)-1-phenylpropan-1-one (2k)14d: yellowish
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(minor) = 15.1 min; 76% ee.
2-((4-Isopropylphenyl)thio)-1-phenylpropan-1-one
yellowish oil (20 mg, 71% yield), (SiO
(2e):
1
2
-chromathography, 5%
t
2
1
(
v/v) ethyl acetate / petroleum ether); H NMR (400 MHz,
CDCl
=
3
): δ = 7.97 (dd, J = 8.4, 1.3 Hz, 2H), 7.57 (m, 1H), 7.46 (t, J
oil (22 mg, 88% yield), (SiO
acetate / petroleum ether); H NMR (400 MHz, CDCl
2
-chromathography, 5% (v/v) ethyl
1
8.3 Hz, 2H), 7.33 – 7.25 (m, 2H), 7.15 (d, J = 8.0 Hz, 2H), 4.60
3
): δ =
(
q, J = 6.9 Hz, 1H), 3.03 – 2.80 (m, 1H), 1.54 (d, J = 6.8 Hz, 3H),
8.03 (dd, J = 8.4, 1.4 Hz, 2H), 7.60 – 7.56 (m, 1H), 7.50 – 7.46
(m, 2H), 4.39 (q, J = 6.9 Hz, 1H), 2.80 – 2.73 (m, 1H), 1.98 – 1.93
(m, 1H), 1.86 – 1.84 (m, 1H), 1.76 – 1.68 (m, 2H), 1.60 (d, J = 6.9
1
3
1
1
.25 (d, J = 7.0 Hz, 6H) ppm; C{ H} NMR (101 MHz, CDCl
3
): δ
=
3
196.4, 149.8, 135.8, 135.1, 133.0, 128.7, 128.5, 128.2, 127.1, 46.3,
3.8, 23.9, 23.8, 16.9 ppm; HRMS (ESI-TOF) m/z: [M + Na]
+
13
1
Hz, 3H), 1.60 – 1.54 (m, 1H), 1.42 – 1.18 (m, 5H) ppm; C{ H}
NMR (101 MHz, CDCl ): δ = 197.5, 135.9, 132.9, 128.6, 128.5, 42.6,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Calcd for C18
H20OSNa 307.1127; Found 307.1126; HPLC analysis:
3
Daicel Chiralcel OJ-H column, n-Hexane: isopropanol = 90:10,
flow rate 1 mL/min, λ = 254 nm (channel 1), 232 nm (channel
2): t
42.0, 34.7, 34.3, 26.0 (x2), 25.6, 17.7 ppm; HRMS (ESI-TOF)
+
m/z: [M + Na] Calcd for C15
H20OSNa 271.1127; Found 271.1119;
1
(major) = 8.6 min, t
2
(minor) = 11.9 min; 75% ee.
HPLC analysis using Daicel Chiralcel OJ-H column, n-Hexane:
isopropanol = 93:7, flow rate 0.5 mL/min, λ = 254 nm (channel
1), 232 nm (channel 2): t (major) = 11.6 min, t (minor) = 15.2
1 2
2-((4-Methoxyphenyl)thio)-1-phenylpropan-1-one
(2f):
white solid (23 mg, 85 % yield), (SiO
(
CDCl
2
-chromathography, 10%
1
v/v) ethyl acetate / petroleum ether); H NMR (400 MHz,
min; 68% ee.
3-(Phenylthio)butan-2-one (2l)14d: yellowish oil (17 mg, 92%
3
): δ = 8.00 – 7.97 (m, 2H), 7.61 – 7.56 (m, 1H), 7.50 – 7.46
(
m, 2H), 7.30 – 7.27 (m, 2H), 6.84 – 6.82 (m, 2H), 4.52 (q, J =
yield), (SiO
petroleum ether); H NMR (400 MHz, CDCl
2
-chromathography, 5% (v/v) ethyl acetate /
1
3
1
1
6
.8 Hz, 1H), 3.82 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H) ppm; C{ H}
): δ = 196.0, 160.6, 137.6, 135.9, 132.9,
28.6, 128.6, 121.4, 114.5, 55.3, 46.3, 16.5 ppm; HRMS (ESI-TOF)
3
): δ = 7.42 – 7.39
NMR (101 MHz, CDCl
3
(m, 2H), 7.35 – 7.30 (m, 3H), 3.79 (q, J = 7.0 Hz, 1H), 2.30 (s,
13
1
1
3H), 1.44 (d, J = 7.1 Hz, 3H) ppm; C{ H} NMR (101 MHz,
CDCl ): δ = 205.6, 132.8, 132.6, 129.1, 128.0, 52.1, 26.3, 16.1 ppm;
HRMS (ESI-TOF) m/z: [M + Na] Calcd for C10
+
m/z: [M + Na] Calcd for C16
95.0760; HPLC analysis: Daicel Chiralcel OJ-H column, n-
Hexane: isopropanol = 90:10, flow rate 1 mL/min, λ = 254 nm
(channel 1), 232 nm (channel 2): t (major) = 50.9 min, t
minor) = 58.3 min; 74% ee.
-((4-Bromophenyl)thio)-1-phenylpropan-1-one (2g): white
16
H O
2
SNa 295.0763; Found
3
+
2
H12OSNa
180.0609; Found 180,0602; HPLC analysis using Daicel
Chiralcel OJ-H column, n-Hexane: isopropanol = 90:10, flow
rate 0.3 mL/min, λ = 254 nm (channel 1), 232 nm (channel 2):
1
2
(
2
t
1
(major) = 47.0 min, t
2-(Phenylthio)-1-(p-tolyl)propan-1-one (2m): yellowish oil
2
(minor) = 49 min; 20% ee.
solid (23 mg, 70% yield), (SiO
ethyl acetate / petroleum ether); H NMR (400 MHz, CDCl
2
-chromathography, 5% (v/v)
1
3
):
(20 mg, 80% yield), (SiO
acetate / petroleum ether); H NMR (400 MHz, CDCl
2
-chromathography, 5% (v/v) ethyl
1
δ = 7.98 – 7.96 (m, 2H), 7.62 – 7.58 (m, 1H), 7.51 – 7,47 (m, 2H),
.42 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 4.64 (q, J = 6.9
3
): δ =
7
7.88 (d, J = 8.4 Hz, 2H), 7.39 – 7.37 (m, 2H), 7.33 – 7.26 (m, 5H),
4.64 (q, J = 6.8 Hz, 1H), 2.44 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H)
1
3
1
Hz, 1H), 1.54 (d, J = 6.9 Hz, 3H) ppm; C{ H} NMR (101 MHz,
13
1
CDCl
3
): δ = 195.9, 136.2, 135.5, 133.2, 132.1, 130.6, 128.6, 128.7,
ppm; C{ H} NMR (101 MHz, CDCl
3
): δ = 196.0, 143.9, 134.4,
+
1
23.3, 46.0, 16.9. ppm; HRMS (ESI-TOF) m/z: [M + Na] Calcd
133.1, 132.0, 129.3, 128.9, 128.8, 128.5, 46.2, 21.7, 17.1 ppm.]; HRMS
+
for C15
H13BrOSNa 342.9763; Found 342.9756; HPLC analysis:
(ESI-TOF) m/z: [M + Na] Calcd for C16H16OSNa 279.0814;
Daicel Chiralcel AD column, n-Hexane: isopropanol = 95:5,
flow rate 1 mL/min, λ = 254 nm (channel 1), 232 nm (channel
2
Found 279.0808; HPLC analysis using Daicel Chiralcel OJ-H
column, n-Hexane: isopropanol = 90:10, flow rate 1 mL/min, λ
): t
2
1
(major) = 7.9 min, t
-((4-Fluorophenyl)thio)-1-phenylpropan-1-oneone (2h) :
2
(minor) = 8.8 min; 64% ee.
= 254 nm (channel 1), 232 nm (channel 2): t
(minor) = 26.0 min; 67% ee.
2-(Phenylthio)-1-(o-tolyl)propan-1-one (2n): yellowish oil
1
(major) = 11.1 min,
2
6
t
2
yellowish oil (22 mg, 86% yield), (SiO
(
CDCl
7
2
-chromathography, 5%
1
v/v) ethyl acetate / petroleum ether); H NMR (400 MHz,
(19 mg, 74% yield), (SiO
acetate / petroleum ether); H NMR (400 MHz, CDCl
2
-chromathography, 5% (v/v) ethyl
1
3
): δ = 7.97 (dd, J = 8.4, 1.4 Hz, 2H), 7.62 – 7.57 (m, 1H),
3
): δ =
.50 – 7.46 (m, 2H), 7.35 – 7.32 (m, 2H), 7.01 – 6.97 (m, 2H),
.58 (q, J = 6.8 Hz, 1H), 1.52 (d, J = 6.8 Hz, 3H) ppm; C{ H}
7.53 (dd, J = 7.8, 1.3 Hz, 1H), 7.38 – 7.33 (m, 3H), 7.30 – 7.23 (m,
4H), 7.22 – 7.17 (m, 1H), 4.55 (q, J = 6.9 Hz, 1H), 2.46 (s, 3H),
13
1
4
1
13
1
NMR (101 MHz, CDCl
3
): δ = 195.9, 163.4 (d, JC-F = 249.7 Hz),
3
1.57 (d, J = 7.0 Hz, 3H) ppm; C{ H} NMR (101 MHz, CDCl ): δ
3
4
1
37.5 (d, JC-F = 8.4 Hz), 135.7, 128.6, 126.34 (d, JC-F = 3.5 Hz),
= 200.4, 138.6, 137.4, 133.8, 132.8, 131.8, 131.2, 128.9, 128.2, 127.9,
2
+
116.0 (d, JC-F = 21.9 Hz), 46.1, 16.7 ppm; HRMS (ESI-TOF) m/z:
125.4, 49.7, 20.9, 17.1 ppm; HRMS (ESI-TOF) m/z: [M + Na]
+
[M + Na] Calcd for C15
HPLC analysis using Daicel Chiralcel OJ-H column, n-Hexane:
isopropanol = 90:10, flow rate 1 mL/min, λ = 254 nm (channel
H13OFSNa 283.0563; Found 283.0567;
Calcd for C16H16OSNa 279.0814; Found 279.0810; HPLC
analysis: Daicel Chiralcel OJ-H column, n-Hexane:
isopropanol = 90:10, flow rate 1 mL/min, λ = 254 nm (channel
1
), 232 nm (channel 2): t
min; 64% ee.
-Phenyl-2-(o-tolylthio)propan-1-one (2j): yellowish oil (19
1
(major) = 13.1 min, t
2
(minor) = 22.2
1), 232 nm (channel 2): t
1
(major) = 11.3 min, t
2
(minor) = 21.1
min. 70% ee.
1
2-(phenylthio)-1-(thiophen-3-yl)propan-1-one
(2o):
mg, 75% yield), (SiO
acetate / petroleum ether); H NMR (400 MHz, CDCl
(
7
2
-chromathography, 5% (v/v) ethyl
yellowish oil (14 mg, 57% yield), (SiO
(v/v) ethyl acetate / petroleum ether); H NMR (400 MHz,
2
-chromathography, 5%
1
1
3
): δ = 7.91
dd, J = 8.4, 1.3 Hz, 2H), 7.59 – 7.5 (m, 1H), 7.46 – 7.41 (m, 2H),
.36 (d, J = 7.4 Hz, 1H), 7.24 – 7.19 (m, 2H), 7.15 – 7.11 (m, 1H),
3
CDCl ): δ = 8.06 (dd, J = 2.9, 1.3 Hz, 1H), 7.58 (dd, J = 5.1, 1.3 Hz,
1H), 7.40 – 7.38 (m, 2H), 7.35 – 7,29 (m, 4H), 4.42 (q, J = 6.9
13
1
4
.68 (q, J = 6.9 Hz, 1H), 2.34 (s, 3H), 1.58 (d, J = 6.9 Hz, 3H)
Hz, 1H), 1.54 (d, J = 6.9 Hz, 3H) ppm; C{ H} NMR (101 MHz,
1
3
1
ppm; C{ H} NMR (101 MHz, CDCl
3
): δ = 196.8, 141.5, 135.6,
CDCl
3
): δ = 191.0, 140.4, 134.6, 132.7, 131.8, 129.0, 128.7, 127.5,
+
134.5, 133.2, 131.9, 130.5, 128.6, 128.6, 128.5, 126.5, 46.1, 21.0, 17.1
ppm; HRMS (ESI-TOF) m/z: [M + Na] Calcd for C16
126.3, 48.2, 16.9 ppm; HRMS (ESI-TOF) m/z: [M + Na] Calcd
+
H16OSNa
2
for C13H12OS Na 271.0222; Found 271.0216; HPLC analysis:
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The Journal of Organic Chemistry
Page 8 of 10
2
Daicel Chiralcel AD column, n-Hexane: isopropanol = 95:5,
flow rate 0.5 mL/min, λ = 254 nm (channel 1), 232 nm (channel
2): t (major) = 17.9 min, t (minor) = 19.3 min; 70% ee.
(a) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. A
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Graphical Journey of Innovative Organic Architectures That Have
Improved Our Lives. J. Chem. Educ. 2010, 87, 1348. (b) Scott, K. A.;
Njardarson, J. T. Analysis of US FDA-Approved Drugs Containing
Sulfur Atoms. Top. Curr. Chem. 2018, 376, 5.
1
2
Preparation of 1-phenyl-2-(m-tolylthio)propan-1-one
2a) at 1 mmol scale. RhCl .H O (5.2 mg, 2.5 mol% ) and (S)-
3
a) Back, T. G.; Baron, D. L.; Yang, K. Desulfurization with
(
3
2
Nickel and Cobalt Boride: Scope, Selectivity, Stereochemistry, and
Deuterium-Labeling Studies. J. Org, Chem. 1993, 58, 2407. b)
Canestrari, D.; Lancianesi, S.; Badiola, E.; Strinna, C.; Ibrahim, H.;
Adamo, M. F. A. Desulfurative Chlorination of Alkyl Phenyl
Sulfides. Org.Lett. 2017, 19, 918.
DIFLUORPHOS (51.2 mg, 7.4 mol%) were weighed and
transferred to a Schlenk-tube. Then, 2.5 mL of dry toluene
solvent was added and stirred at room temperature for 15
minutes. Next, a solution of allylic alcohol 1a (1 mmol) in
toluene (2.5 mL) was added and the reaction mixture was
heated at 55 °C (oil bath) for 36 h. After completion of the
reaction, the reaction mixture was filtered through a plug of
silica washed with EtOAc. The crude was evaporated under
reduced pressure and the residue was purified by silica-gel
column chromatography (5% (v/v) ethyl acetate / petroleum
ether), to afford the desired ketone (205 mg, 81% yield); HPLC
analysis: Daicel Chiralcel OJ-H column, n-Hexane:
isopropanol = 99:1, flow rate 1 mL/min, λ = 254 nm (channel
4
a) Liebeskind, L. S.; Srogl, J. Heteroaromatic
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Thioether−Boronic Acid Cross-Coupling under Neutral Reaction
Conditions. Org. Lett. 2002, 4, 979; b) Arambasic, M.; Majhail, M.
K.; Straker, R. N.; Neuhaus, J. D.; Willis, M. C. A Rhodium-
Catalysed
Sonogashira-Type
Coupling
Exploiting
C–S
Functionalisation: Orthogonality with Palladium-Catalysed
Variants. Chem. Commun. 2009, 55, 2757.
5
Abramovitch, A.; Varghese, J. P.; Marek, I. α-Sulfinyl
Carbanions as A New Source of Olefins. Org. Lett. 2004, 6, 621-
1
), 232 nm (channel 2): t
1
(major) = 8.5 min, t
2
(minor) = 9.0
623.
6
a) Screttas, C. G.; Micha-Screttas, M. Hydrolithiation of
min; 74% ee.
Alpha-Olefins by
a
Regiospecific Two-Step process.
Transformation of Alkyl Phenyl Sulfides to Alkyllithium Reagents.
J. Org. Chem. 1978, 43, 1064-1071. b) Foubelo, F.; Yus, M. Chem.
Soc. Rev., 2008, 8, 5682.
ASSOCIATED CONTENT
Experimental details and characterization data, NMR spectra
and HPLC chromatograms, are available free of charge via the
Internet at http://pubs.acs.org.
7
Hugenberga, V.; Fröhlich, R. Haufe, G. Oxidative
Desulfurization–Fluorination of Thioethers. Application for the
Synthesis of Fluorinated Nitrogen Containing Building Blocks.
Org. Biomol. Chem. 2010, 106.
AUTHOR INFORMATION
Corresponding Author
8
For reviews in asymmetric sulfenylation, see: (a) Wang, W.;
Zhang, X. C–X Bond Formation: Organocatalytic α-Sulfenylation
and α-Selenenylation Comprehensive Chirality. 2012, 6, 518. (b)
Wladislaw, B.; Marzorati, L.; Di Vitta, C. Sulfanylation Reactions
of Carbonyl Compounds and Carboxylic Acid Derivatives
Employing Sulfur Electropfflles. A Review. Org. Prep. Proced. Int.
*E-mail: joseph.samec@su.se.
ORCID
Joseph S. M. Samec: 0000-0001-8735-5397
2
007, 39, 447. (c) Zhao, X.; Shen, J.; Jiang, Z. Catalytic Asymmetric
α-Sulfenylation: A New and Efficient Pathway to Access Chiral C-S
Notes
Bonds. Mini-Rev. Org. Chem. 2014, 11, 424
9
(
a) Aveniente, M.; Pinto, E: F.; Santos, L. S.; Rossi-Bergmann,
The authors declare no competing financial interest.
ACKNOWLEDGMENT
B.; Barata, L. S. Structure–Activity Relationship of
Antileishmanials Neolignan Analogues. Bioorg. Med. Chem 2007,
15, 7337. (b) Krapcho, J.; Turk, C. F. 4-[3-(Dimethylamino)Propyl]-
3
,4-Dihydro-2-(1-Hydroxyethyl)-3-Phenyl-2h-1,4-Benzothiazine
Financial support from the Swedish Research Council
and Related Compounds. New Class of Antiinflammatory Agents.
J. Med. Chem. 1973,16, 776. (c) Siatra-Papastaikoudi, T.; Tsotinis,
A.; Chinou, I.; Roussakis, C. Synthesis and Anticancer Activity of
New Phenyl-Ring Substituted 4-Morpholino-1-Phenylthio-2-
Butanones [Mannich Bases]. Farmaco, 1994, 49, 2217. (d)
Hartman, I.; Gillies, A. R.; Arora, S.; Andaya, C.; Royapet, N.;
Welsh, W. J.; Wood, D. W.; Zauhar, R. J. Application of Screening
Methods, Shape Signatures and Engineered Biosensors in Early
Drug Discovery Process. Pharm. Res. 2009, 26, 2247.
(
Formas) and Stiftelsen Olle Engkvist Byggmästare is
gratefully acknowledged.
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000, 100, 3205. (b) Chauhan, P.; Mahajan, S.; Enders, D.
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0
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A slightly loss of enantioselectivity was observed when using
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Insert Table of Contents artwork here
F O
OH
RhCl3.H2O
O
F
F
O
F
L*
PPh2
PPh2
Ar
Ar
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O
S
S
O
L* = (S)-FLUOROPHOS
er = 75:25->99:1
yields = 57-90
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